Age-associated changes in immune function in humans and animals are quite important with regard not only to the general health of aged persons but also to the general features of the immune system itself. Elderly subjects have been shown to be more susceptible to viral and bacterial infections and are believed to be more susceptible to cancer. There have been a number of hypotheses for the diminished immune responses observed in elderly subjects including involution of the thymus, active immunosuppression, replication senescence of immune cells, cellular signaling defects, and alterations in cytokine expression profiles. However, despite the many findings on alterations in immune function with age, very little is known about the why such changes occur and how alterations in immune cell subsets and their activities influence immune function in the elderly and/or during various disease states. The ongoing work utilizes either peripheral white blood cells obtained from normal healthy volunteers of different ages or cells from aged rodents and primates to gain insight into the biological, biochemical, and molecular mechanisms underlying age-associated changes in human immune function. In comparison with immune cells obtained from younger individuals, aged leukocytes also display distinctive patterns of protein phosphorylation, cytokine synthesis and gene expression, effects on cell migration and trafficking, and cell-cycle progression. One of our recent findings demonstrated that aged lymphocytes produce more adenosine than younger T cells, which interacts with the adenosine 2A receptor mediating immunosuppression. The precise role of adenosine in immunosenescence is currently being explored. In addition, we have found that various immunotherapeutic strategies are quite toxic for middle aged and old mice compared to younger animals and that this increase in morbidity is associated with macrophages, TNF and adiposity. Antagonists to TNF-R activity prevented these toxicities and provided a greater effect on anti-tumor effects in older animals. These studies suggest that combinational therapies may be necessary for immunotherapeutic treatments in older animals and possibly humans. Overall, as immune subsets (e.g., T cells, macrophages, NK cells) have been shown to be dramatically change in numbers and percentages with age and during various disease states, we believe that more detailed analysis of these subsets, their cytokine expression profile and their role in disease progression will not only yield valuable information about the immune deficits associated with aging and disease but may also lead to possible immunotherapeutic interventions to boost immune responses.